A Marshfield Clinic scientist is searching for genetic and environmental causes of Alzheimer’s disease as a first step toward developing diagnostic markers to identify people at risk before they develop the disease.

Nader Ghebranious, Ph.D., director of the Molecular Diagnostics Laboratory, Marshfield Laboratories, is using the anonymous database of DNA collected for the Personalized Medicine Research Project (PMRP) conducted by Marshfield Clinic Research Foundation (MCRF) to find Alzheimer’s disease study participants. This study is being funded by Marshfield Clinic.

About 10 percent of people age 65 or older and half of those 85 or older in the United States have late-onset Alzheimer’s disease. The degenerative brain disorder impairs memory and judgment as well as the ability to perform once easy tasks. Sometimes, a person with Alzheimer’s disease has mood swings and becomes depressed and irritable. It may be difficult for a person with Alzheimer’s disease to enjoy activities and people that once were pleasurable.

PMRP collected DNA from more than 18,000 people who live in central and northern Wisconsin and who receive all or most of their health care from Marshfield Clinic. Using the electronic medical record developed by Marshfield Clinic and in use for more than a decade, researchers will be able to link anonymous health histories with genetic information to understand the role specific genes play in disease. Building on this research, in the future a physician will be able to diagnose and prescribe medication or treatment based on genetic information and even counsel a patient to make lifestyle changes to prevent disease altogether.

This project requires 150 people with Alzheimer’s disease and about 300 people of similar age who do not have the disease. “Association studies like this require us to match people who have the illness with those who do not,” Ghebranious said.

Using the PMRP database of DNA, Ghebranious will identify people who have been diagnosed with Alzheimer’s disease. The PMRP is expanding its recruitment to nursing homes; more people with Alzheimer’s disease will qualify for the study. The vast majority of people in nursing homes have late-onset Alzheimer’s disease, he said.

Because the disease is extremely complex, researchers believe that more than one genetic anomaly and perhaps environmental factor leads to Alzheimer’s disease. Ghebranious is studying four specific genes and their connection to the disease process.

“It is important to consider more than one factor because one gene variant by itself may not confer a detectable risk of getting the disease,” he said. “It is when multiple gene variants act together synergistically that probability for disease increases.”

A person with even the most probable genetic link, APOE4, a gene variant of a protein called APOE (Â-po-ç) that functions in the transport of cholesterol and phospholipids, is estimated to have five times higher risk of developing Alzheimer’s disease.

A second gene, called Cytochrome P46, which modifies cholesterol, may be associated with Alzheimer’s disease and the way the body removes cholesterol from the brain.

The other two genes, Oxidized LDL receptor 1 and Angiotensin 1-converting enzyme, are tied to the way the brain cells bind to APOE and reduce buildup of harmful proteins, known as plaques, in the brain, respectively.

Environmental factors likely contribute to Alzheimer’s disease as well. Two specific potentially protecting factors - cigarette smoking and use of cholesterol-lowering drugs called statins - will be considered in this study.

“There are controversial findings in previous studies on smoking,” Ghebranious said. “Some earlier research has suggested nicotine decreases the brain plaque associated with Alzheimers disease, results of a new mouse study point to the opposite conclusion. More studies are needed.”

Other studies have indicated that people who use statins have less risk of Alzheimer’s disease than those who do not, but no studies have proven it conclusively. Other environmental factors (e.g., infections, metals, industrial or other toxins) may trigger oxidation, inflammation and the disease process, particularly in people with genetic susceptibility to Alzheimers disease.

It is known that a “heart healthy” diet and exercise also lower risk of Alzheimer’s disease, probably by lowering cholesterol.

Ghebranious’ study is unique because other researchers do not have access to complete medical histories as researchers at Marshfield Clinic do, Ghebranious said. Having the history of medications people have taken, their illnesses and health status are important to linking genetics, environment and resulting disease.

In addition, the Wisconsin population that has participated in the PMRP is for the most part ethnically homogeneous. Having this kind of population in the study reduces the “noise” due to genetic variations among races.

“It is as if we can turn down the static and concentrate on the issues at hand,” he said.

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